Rifampicin Explorative PK Study for Tuberculous Meningitis Comparing Oral and Intravenous Preparation (REMOVER)

• Pharmacokinetic profile of several rifampicin dose [ Time Frame: Day 2 and Day 14; 6 time points for blood analysis, and 1 time point for CSF analysis ] [ Designated as safety issue: Yes ]
  We will measure plasma drug concentration at hour 0, 1, 2, 4, 8, and 12, while CSF drug concentration will be measured at a single time point i.e. at hour 3-6 post dose. The sampling days will be (1) within the first three days, and (2) at day 14 of the intensified treatment.
  
  

• mortality [ Time Frame: early (1 month) and late (6 months) ] [ Designated as safety issue: No ]
  We will measure early and late mortality
  
  

Introduction:

In a recent clinical trial the investigators have shown that a higher dose of rifampicin administered intravenously (600 mg iv) during the first 2 weeks of treatment is safe and associated with a survival benefit in adults with TB meningitis. An oral (rather than iv) dose would help implementation of intensified treatment for TB meningitis. However, it is hard to predict what oral dose of rifampicin will result in rifampicin exposures similar to 600 mg iv, due to differences in bio-availability (oral vs. iv) and the unpredictable dose-concentration relationship (nonlinear pharmacokinetics of rifampicin). Therefore the investigators aim to examine the pharmacokinetic of 2 higher doses of rifampicin (750 mg and 900 mg) given orally, and compare the pharmacokinetic profiles with the result of our previous study using 600 mg rifampicin iv.

General Objective:

To help establish the optimized treatment regimen for TB meningitis

Specific Objectives:

1. To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar to exposures after intravenous rifampicin 600 mg during the first two days of treatment
2. To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar to exposures after 14 days of treatment (stabilized rifampicin concentrations, i..e steady-state)
3. To evaluate the safety and tolerability of high dose of oral rifampicin
4. To evaluate neurological response and mortality after 2 weeks of treatment with high dose rifampicin

Study Design:

Explorative pharmacokinetic study; randomized, three-arm, two-period evaluation.

Study procedure:

After diagnosis of TB meningitis, eligible patients will be randomized to get either oral 750 mg, oral 900 mg, or iv 600 mg rifampicin for 14 days in combination with standard oral TB drugs (isoniazid 300 mg/day, ethambutol 750 mg/day, and pyrazinamide 1500mg/day) and adjuvant dexamethasone i.v. and pyridoxine.

Serial blood samples will be taken 6 times from 0, 1, 2, 4, 8, and 12 hour after drug administration at the first or second day of treatment and at day 14 (steady-state). Single cerebrospinal fluid (CSF) sample will be taken 3-6 hours after administration at the same day of blood sampling days.